Pneumococcus causes many clinically-important diseases in adults, including pneumonia and septicemia. Pneumococcal conjugate vaccines administered to children have nearly eliminated both disease and colonization caused by the targeted serotypes not only in children but also in adults because children no longer transmit these serotypes. However, serotypes not targeted by the vaccine have increased and will continue to increase as causes of disease, particularly in adults. As a result, there is a large remaining burden of disease that cannot be effectively prevented with the currently-available conjugate vaccines. Consequently, there is a critical need for a new conjugate vaccine formulation that targets the serotypes that will cause the most disease in adults. The proposed projects will address a major challenge-forecasting which of the remaining 80+ serotypes that are not included in the current conjugate vaccines are most likely to become important causes of disease in adults in the future. To make such forecasts about disease patterns in adults, it is necessary to understand the determinants of serotype frequency among the healthy children who carry pneumococcus in the nasopharynx (the main source of exposure for adults). Likewise, it is critical to understand how changes in the serotype frequency among healthy vaccinated children influence the frequency of serotype-specific disease in adults. To answer these critical questions, we will first use a novel high- throughput in vitro assay of serotype competition (a known correlate of serotype frequency among carriers) in which large numbers of serotypes will be grown in nutrient-limited media. The relative frequency of the serotypes in these competitions will be tracked using targeted Illumina sequencing of the capsular genes. We will fit regression models to compare the in vitro competitiveness of the serotypes with the real world frequency of serotypes colonizing Navajo children in the pre-vaccine years. We will then assess the validity of this model by testing whether serotype competitiveness could have predicted the frequency of serotypes colonizing children after introduction of the first or second generation conjugate vaccines (PCV7 and PCV13). Because serotypes differ in their capacity to cause disease, it is important to know how projected changes in carriage will impact disease rates in adults. Using large clinical databases on carriage and disease from The Navajo Nation and Denmark, we will fit and validate empirical models to determine, for different serotypes, how capacity to cause disease and post-vaccine changes in frequency among pediatric carriers influence disease patterns in adults with or without underlying diseases. Finally, we will combine our projections of changes in carriage (based on the experimental data) with the models linking carriage in children and disease in adults to forecast the serotypes most likely to become important causes of disease in adults. These studies will provide important new information that will inform the selection of which serotypes should be included in a pneumococcal conjugate vaccine for use in adults in the future.